Application of Genetics to the Prevention of Colorectal Cancer
A first-degree relative of an individual with colorectal cancer is on average at about a twofold increased risk. This could not occur without there being strong underlying risk factors that are correlated in relatives. About 90% of colorectal cases occur in people who are above median familial/genetic risk, so there is great potential to use genetics to prevent colorectal cancer. Two rare inherited syndromes have been identified: familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC). The former appears to be mostly due to mutations in the APC gene, and the latter to mutations in mismatch repair (MMR) genes, so it would be better named as hereditary mismatch repair deficiency (HMRDS). By fully characterising a population based series of early-onset cases, we have shown that MMR gene mutation carriers and their relatives can be more efficiently identified by characterising the tumours of early on set cases, independently of their cancer family history, using immunohistochemistry (IHC)—not microsatellite instability (MSI) testing. This identifies the specific MMR gene likely to be involved, reducing the costs of mutation testing. Identification of genetically susceptible individuals using the tumour phenotype of affecteds, rather than family cancer history, could become the standard approach of cancer genetic services in the twenty-first century, and could lead to cancer prevention in individuals who are at a high genetic risk when young. There is an urgent need for research on the efficacy and optimisation of surveillance procedures in these high-risk individuals, and identification of the environmental, lifestyle and other genetic factors that exacerbate, or ameliorate, risk in mutation carriers.
KeywordsColorectal Cancer Mutation Carrier Lynch Syndrome Mutation Testing Familial Aggregation
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- Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN, Srivastava S (1998) A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58:5248–5257PubMedGoogle Scholar
- Jenkins MA, Baglietto L, Dite GS, Jolley DJ, Southey MC, Whitty J, Mead LJ, St John DJ, Macrae FA, Bishop DT, Venter DJ, Giles GG, Hopper JL (2002) After hMSH2 and hMLH1—what next? Analysis of three-generational, population-based, early-onset colorectal cancer families. Int J Cancer 102:166–171PubMedCrossRefGoogle Scholar
- Lindor NM, Burgart LJ, Leontovich O, Goldberg RM, Cunningham JM, Sargent DJ, Walsh-Vockley C, Petersen GM, Walsh MD, Leggett BA, Young JP, Barker MA, Jass JR, Hopper J, Gallinger S, Bapat B, Redston M, Thibodeau SN (2002) Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol 20:1043–1048PubMedCrossRefGoogle Scholar
- Peto J (1980) Genetic predisposition to cancer. In: Cairns J, Lyon JL, Skolnick MH (eds) Banbury Report nu4; cancer incidence in defined populations. Cold Spring Harbor Laboratories, Cold Spring Harbor, New York, pp 203–213Google Scholar
- Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Ruschoff J, Fishel R, Lindor NM, Burgart LJ, Hamelin R, Hamilton SR, Hiatt RA, Jass J, Lindblom A, Lynch HT, Peltomaki P, Ramsey SD, Rodriguez-Bigas MA, Vasen HF, Hawk ET, Barrett JC, Freedman AN, Srivastava S (2004) Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261–268PubMedGoogle Scholar